Many cytokine-mediated diseases and conditions are associated with excessive or unregulated production or activity of one or more cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 8 (IL-8). IL-1 and TNF are important proinflammatory cytokines, which along with several other related molecules, mediate inflammatory cellular response in a wide variety of diseases and conditions. Proinflammatory cytokines such as IL-1 and TNF stimulate other inflammatory mediators such as nitric oxide, cyclooxygenase-2, matrix metalloproteinases. The inhibition of these cytokines is consequently both directly and indirectly beneficial in controlling, reducing and alleviating many of these disease states.
Elevated levels of proinflammatory cytokines are implicated in many disease states, including rheumatoid arthritis (Dinarello, C. A., et al. 1984, Rev. Infect. Disease 6:51; Maini, R. E. 1999, The Lancet 354:1932; Weinblatt, M. E. 1999, New Eng. J. Med. 340:253), osteoarthritis (Pelletier and Pelletier 1989, J. Rheum. 16:19; Pelletier, et al. 1993, Am. J. Path. 142:95; Farahat, et al. 1993, Ann. Rheum. Dis. 52:870; Tiku, et al. 1992, Cell Immunol. 140:1; Webb, et al. 1997, O. & C. 5:427; Westacott, et al. 2000, O. & C. 8:213), diabetes (McDaniel, et al. 1996, Proc. Soc. Exp. Biol. Med. 211:24), HIV/AIDS (Kreuzer, et al. 1997, Clin. Exp. Immunol. 45:559), acute and chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al. 1997, British J. Rheum. 35:334; Stack, W. A., et al. 1997, The Lancet 349:521); congestive heart failure Han et al. 2000, Trends Cardiovasc. Med. 10:19; Hunter et al. 1999, N. Engl. J. Med. 341:1276; Behr et al. 2000, Circ. 102:II-289; Shimamoto et al. 2000, Circ:102:II-289; Aukrust et al. 1999, Am. J. Cardiol. 83:376, hypertension (Singh, et al. 1996 J. Hypertension 9:867), chronic obstructive pulmonary disease, septic shock syndrome (Dinarello, C. A. 1995, Nutrition 11:492), tuberculosis, adult respiratory distress, asthma (Renzetti, et al. Inflammation Res. 46:S143), atherosclerosis (Elhage, et al. 1998, Circulation 97:242), muscle degeneration, periodontal disease (Howells 1995, Oral Dis. 1:266), cachexia, Reiter's syndrome, gout, acute synovitis, eating disorders including anorexia and bulimia nervosa (Holden, et al. 1996, Med. Hypothesis 47:423), fever, malaise, myalgia and headaches (Beisel 1995 Am. J. Clin. Nutr. 62:813). Inhibition of proinflammatory cytokine production, therefore, may offer the opportunity to treat or prevent a wide range of diseases and conditions involving elevated levels of proinflammatory cytokines.
Numerous small molecule inhibitors of cytokine production have been disclosed. (See Salituro, F. G. et al. 1999, 6, 807-823 and references cited therein). In particular, 1,2,4-triazoles (WO 00/10563 and WO 97/47618), isoxazoles (WO 01/12621), and imidazoles (WO 00/26209, WO 99/03837 and references therein) have been disclosed. However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have recently been reported (Foster, M. L. et al., Drug News Perspect, 2000, 13(8), 488-497 and Adams, J. L. et al., Bioorg Med Chem Lett, 1998, 8, 3111-3116). In light of the this potential toxicity and the risks associated with developing human drugs, a continuing need exists for potent new small molecule inhibitors of cytokine production with improved pharmacokinetic and safety profiles.
All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.